Platelet-Activating Factor Antagonist BN 50730 Attenuates Hypoxic-Ischemic Brain Injury in Neonatal Rats

Abstract

Platelet-activating factor (PAF) is a lipid derived from breakdown of cell membranes that is postulated to be a mediator of cerebral ischemic injury. PAF regulates CNS gene transcription via intracellular binding sites. To test the hypothesis that PAF mediates CNS injury in part by modulating gene transcription, we evaluated the neuroprotective efficacy of the drug BN 50730, an antagonist of the intracellular (microsomal) CNS PAF binding site, in the neonatal rat model of unilateral cerebral hypoxiaischemia. Seven-day-old rats underwent right carotid ligation followed by a 2.5-h exposure to 8% O 2 , and were then treated with BN 50730 (2.5 or 25 mg/kg per dose) or vehicle, at 0 and 2 h after the end of hypoxia. Ipsilateral cortical, striatal, and hippocampal damage was quantitated either 5 d later, or at 5 wk after the insult. Treatment with BN 50730 resulted in approximately 60 -80% reduction in ipsilateral tissue loss at both times. Learning and memory were evaluated 5 wk after insult using the Morris Watermaze place navigation task. Severity of cortical and striatal damage correlated significantly with learning and memory deficits. These results support the hypothesis that PAF is a pathogenetic mediator of hypoxic-ischemic damage in the immature brain. Accumulating evidence suggests that PAF mediates its deleterious effects in the immature CNS via multiple mechanisms. PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent phospholipid mediator with distinct systemic and CNS actions. In the CNS, PAF is synthesized in neurons and microglia (1, 2), and PAF receptors are expressed predominantly in neurons and microglia and, to a lesser extent, on astrocytes and CNS endothelium (3-5). PAF has distinct neuronal actions, as a synaptic messenger, a transcriptional activator, and a critical determinant of normal brain development (6, 7). In addition to these CNS effects, PAF has potent proinflammatory systemic effects (8). PAF accumulates in ischemic CNS tissue in mature and immature animals (9 -12). In mature animals, most reports indicate that PAF receptor antagonist treatment attenuates cerebral ischemic damage (13-16). Several recent studies implicate PAF as a mediator of ischemic injury in the neonatal brain (12, 17).Brain PAF concentrations rise acutely after neonatal cerebral hypoxia-ischemia (12), most likely as a result of breakdown of membrane phospholipids. Treatment with the PAF receptor antagonist BN 52021 (ginkgolide B), beginning either before or immediately after hypoxia exposure, reduced hypoxicischemic brain injury in postnatal d 7 rats (17). Pretreatment with a Ginkgo biloba extract, which includes BN 52021, attenuated posthypoxic-ischemic PAF accumulation (12). These results suggest that PAF contributes to the pathogenesis of neonatal cerebral hypoxic-ischemic injury.PAF could mediate cerebral hypoxic-ischemic injury via either of two distinct neuronal PAF binding sites. Studies in adult rat cerebral cortex subcellular membrane fractions delineate distinct populations of neuronal PAF bind...

Proinflammatory Gene Induction by Platelet-Activating Factor Mediated Via Its Cognate Nuclear Receptor

“…5A). These findings may imply distinct functions for the PAF receptor, depending on its localization as previously proposed (8,9). In addition, C-PAF-induced COX-2 transcription in isolated nuclei seems to be MEK/ERK1/2-and NF-B dependent (Fig.…”

“…Some mechanisms recently uncovered to explain GPCRmediated gene induction implicate endocytosis-associated ␤-arrestin-c-Src interaction leading to downstream activation of Ras and mitogen-activated protein kinases (MAPKs) and possibly metalloprotease-dependent transactivation of receptor tyrosine kinases involving de novo release of their ligand (6). Alternatively, PAF may exert intracellular actions by generating its own formation (7), inferring possible active intracellular binding sites (8,9).…”

“…Enzymes involved in the biosynthesis of PAF, namely cytosolic phospholipase A 2 (cPLA 2 ) and acetyltransferase, have been detected on the nuclear membrane (12,13). Separate functions for the intracellular and cell surface receptors have been suggested using agents that putatively distinguish these receptors (8,9). Specifically, immediate effects have been proposed to be mediated by cell surface receptors, whereas regulation of expression of specific genes may be dependent upon intracellular receptors, consistent with the presence of signaling effectors in nuclei, including G proteins (14,15), ionic channels (16,17), phospholipases (12,18), adenylate cyclase (19), kinases (20), and NF-B (21).…”

Preterm Fetal Hypoxia-Ischemia Causes Hypertonia and Motor Deficits in the Neonatal Rabbit: A Model for Human Cerebral Palsy?

“…Postnatal rats readily sustain large hypoxic-ischemic histopathological lesions but do not exhibit hypertonia (Liu et al, 2001). Hypoxia-ischemia at P7 in rats results in cognitive deficits in short-term retention and swimming escape latency after 6 weeks (Liu et al, 2001).…”

Hipoksik iskemik beyin hasarı oluşturulan yenidoğan sıçanlarda ABT-491 uygulamasının görsel uyarılma potansiyelleri üzerine etkileri

“…Bu amaçla, son y›llarda yap›lan baz› çal›flmalarda PAF antagonistlerinin nöropro-tektif etkisinin oldu¤u gösterilmifltir (14,15). ABT-491 (4-etinil-…”